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NIH Record - National Institutes of Health

NIH Researchers Discover New Eye Disease

Retinal images of a patient with a TIMP3 mutation

Retinal images of a patient with a TIMP3 mutation causing atypical symptoms. While there is visible damage in the retina (dark circles), there is no CNV present.

Photo: NEI

NEI researchers have identified a new genetic disease that affects the macula, a small part of the light-sensing retina needed for sharp, central vision. The findings on this novel, yet-to-be-named macular dystrophy were reported in JAMA Ophthalmology

Macular dystrophies are disorders that usually cause central visual loss because of mutations in several genes, including TIMP3.

For example, people with Sorsby Fundus Dystrophy, a genetic eye disease specifically linked to TIMP3 variants, usually develop symptoms in adulthood. They often have sudden changes in visual acuity due to choroidal neovascularization—new, abnormal blood vessels that grow under the retina, leaking fluid and affecting vision.

TIMP3 is a protein that helps regulate retinal blood flow and is secreted from the retinal pigment epithelium (RPE), a layer of tissue that nourishes and supports the retina’s light-sensing photoreceptors. All TIMP3 gene mutations reported are in the mature protein after it has been “cut” from RPE cells in a process called cleavage.

“We found it surprising that two patients had TIMP3 variants not in the mature protein, but in the short signal sequence the gene uses to ‘cut’ the protein from the cells,” said lead author Dr. Bin Guan. “We showed these variants prevent cleavage, causing the protein to be stuck in the cell, likely leading to retinal pigment epithelium toxicity.”

The research team followed these findings with clinical evaluations and genetic testing of family members to verify that the two new TIMP3 variants are connected to this atypical maculopathy.

“Affected individuals had scotomas, or blind spots, and changes in their maculas indicative of disease, but, for now, they have preserved central vision and no choroidal neovascularization, unlike typical Sorsby Fundus Dystrophy,” said Dr. Cathy Cukras, a medical retina specialist who clinically evaluated the patients.

Dr. Rob Hufnagel, senior author and director of NEI’s Ophthalmic Genomics Laboratory, said, “Discovering novel disease mechanisms, even in known genes like TIMP3, may help patients looking for the correct diagnosis and will hopefully lead to new therapies for them.” 

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